Control of iron absorption by intestinal HIF2 in iron and hematological disorders

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Iron-related disorders affect over a billion people worldwide. Dysregulation of intestinal iron absorption is an essential component of iron-related disorders. Although iron-deficient anemia and hereditary hemochromatosis are on opposite ends of the iron-disorder spectrum with respect to systemic iron levels, they initiate very similar intestinal responses. Hyperabsorption of iron is mediated by the transcription factor hypoxia-inducible factor (HIF)2α. We recently demonstrated a novel hetero-tissue signaling axis that initiates increased intestinal iron absorption in iron-related disorders: liver hepcidin levels decrease, leading to stabilization of the iron exporter ferroportin; the resulting efflux of intestinal iron into the blood triggers HIF2α activation, which leads to a feed-forward cycle of increased iron absorption from the intestinal lumen. We recently found that metabolites produced by gut microbiota are essential regulators of HIF2α expression and activity. The role of the microbial metabolites in the regulation of iron absorption is still unclear. Moreover, how HIF2α selectively regulates iron metabolism-related target genes, but not its other target genes, in iron deficiency and hereditary hemochromatosis is enigmatic. The first on-target HIF2α inhibitor produced promising results in clinical trials with patients with renal cancer; however, it is not known whether HIF2α can be targeted to treat iron-related disorders. For those reasons, research on HIF2α and its role in iron metabolism is needed and likely to lead to novel therapies. The overall objective of this proposal is to define the mechanistic underpinnings of HIF2α-mediated regulation of intestinal iron absorption. On the basis of our preliminary data, we hypothesize that the transcriptional activity and iron-absorptive gene networks activated by HIF2α are regulated in a coordinate fashion by epigenetic reprogramming and microbial metabolites in iron-related disorders. Using a novel reporter mouse model, we discovered specific histone modifications on HIF2α iron target genes. In Aim 1, we will conduct experiments using the same mouse model to determine if cell-autonomous epigenetic reprogramming is critical to regulate intestinal iron absorption. In Aim 2, we will determine if the microbial metabolite axis is the major mechanism regulating HIF2α in iron-deficiency and iron-overload disorders. In Aim 3, we will determine if drugs that inhibit or activate HIF2α provide any benefit alone or in an adjuvant setting in preclinical models of iron-related disorders. Completion of those Aims will (i) uncover mechanisms of HIF2α regulation, (ii) define new metabolic pathways that alter intestinal iron absorption, and (iii) highlight new pathways and potential drug targets.